Due to the recent revision of laws on organ transplantation, a few organ transplants from brain dead patients have been performed in Japan. In one case, seven patients received such benefits from one donor. Hereafter, organ transplantations are expected to increase.
On the other hand, Japanese patients affected by severe cardiovascular diseases, such as, hepatic diseases (acute hepatic failure, hepatic cirrhosis, etc.), cardiac diseases (severe heart failure, cardiomyopathy, cardiac hypertrophy, etc.), renal diseases (renal failure, chronic glomerulonephritis, diabetic nephropathy, pyelonephritis, etc.), pulmonary diseases (pulmonary dysfunction of both lungs, etc.), and pancreatic diseases (treatment of diabetic patients), for whom organ transplantation is vital for therapy, are estimated to increase each year by about 600 heart patients, about 3,000 liver patients, and about 500 lung patients. While the legal aspect is being developed, the lack of transplantable organs is also a real problem that exists at the moment. Similarly, the lack of organs is a serious problem also in the United States, which is an advanced nation in terms of transplantation. In the United States, approximately 4,300 people (1999) are awaiting heart transplantations and approximately 43,000 people (1999) are awaiting renal transplantations. In reality, approximately 800 people and approximately 2,300 people die each year without being able to receive heart and kidney transplantations, respectively.
Tissue (such as skin, cornea and bone) or organ (such as liver, heart, kidney, lung and pancreas) transplantation includes: (1) autotransplantation (autologous transplantation), (2) isotransplantation, (3) allotransplantation, and (4) xenotransplantation.
Autotransplantation refers to the transplantation of a part of an individual to another part of the same individual, and an example is the case of treating a burn by grafting one's own normal skin to the affected area.
Isotransplantation is performed between homogeneous animals. In humans, such a transplantation is performed between monozygotic twins (for example, transplantation of one of the kidneys or liver tissues).
Allotransplantation is performed between two different individuals having different genetic backgrounds, and in humans, such a transplantation is performed between dizygotic twins or between individuals who have absolutely no blood relation to each other.
Xenotransplantation is performed between individuals of different animal species. An example is the case where a tissue or an organ of a chimpanzee or a pig is transplanted into a human.
As mentioned above, allotransplantations from brain dead patients are expected to increase due to the development of legislation relating to organ transplantation. However, in order to resolve the absolute lack of transplantable organs, various investigations are now being actively pursued aiming at practical applications of xenotransplantation, more specifically, the transplantation of tissues or organs from non-human mammals such as pigs to humans.
While the issue of the lack of transplantable tissues and organs is expected to be resolved by the development of laws on brain death and transplantation, and by the improvement of xenotransplantation techniques, there is another extremely large obstacle in treating diseases by allotransplantation and xenotransplantation. More specifically, the obstacle is severe immunological rejection (graft rejection) in recipients that occurs after the transplantation of tissues or organs from donors.
Graft rejection refers to various immune responses that try to reject and eliminate a graft (a part of a living body that is transplanted, a cell, a tissue, or an organ) from a donor whose genetic background is different to that of the recipient (i.e., allotransplantation or xenotransplantation) since the recipient recognizes the graft as a foreign substance. The immune responses that accompany this transplantation can be classified into: (1) hyper-acute rejection, which is a strong rejection occurring immediately after transplantation; (2) acute rejection, which is observed within a few months after transplantation; and (3) chronic rejection observed several months after transplantation. Furthermore, although cellular immunity due to immunocompetent cells represented by T cells, and humoral immunity due to antibodies occur in an intricately coordinated manner, the main response is by cellular immunity.
As a result of graft rejection, the graft ultimately becomes necrotic and falls off. Furthermore, the recipient develops not only severe systemic symptoms such as fever, leukocytosis and fatigue, but also swelling and tenderness at the transplantation site. Furthermore, severe complications such as infections may occur.
In particular, when transplanting a xenogenic graft such as that from a pig, the serious problem of hyper-acute rejection occurs whereby the graft is rejected within minutes.
A limited number of immunosuppressive agents that suppress the function of immunocompetent cells are used to suppress the immunological rejection (graft rejection) accompanying such transplantations, because the immunological rejection caused by allotransplantation is mainly due to cellular immunity. Such immunosuppressive agents include cyclosporin (CsA); tacrolimus (FK-506); azathioprine (AZ); mycophenolate mofetil (MMF); mizoribine (MZ); leflunomide (LEF); adrenocortical steroids (also known as adrenocortical hormones, corticosteroids, corticoids) such as prednisolon and methylprednisolon; sirolimus (also known as rapamycin); deoxyspergualin (DSG); and FTY720 (chemical name: 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride).
CTLA4 and CD28 which are molecules responsible for transducing costimulatory signals necessary for the activation of T cells (costimulatory signal transduction molecules), and especially CTLA4 drugs that use the soluble region of CTLA4 and the gene encoding it are also being clinically developed as immunosuppressive agents.
On the other hand, recently, similarly to CTLA4 and CD28 which are costimulatory signal-transducing molecules, a molecule called activation inducible lymphocyte immunomodulatory molecule (AILIM; human, mouse, and rat; Int. Immunol., 12(1), p. 51-55, 2000; also called Inducible co-stimulator (ICOS; human; Nature, 397(6716), p. 263-266, 1999); J. Immunol., 166(1), p. 1, 2001; J. Immunol., 165(9), p. 5035, 2000; Biochem. Biophys. Res. Commun., 276(1), p. 335, 2000; Immunity, 13(1), p. 95, 2000; J. Exp. Med., 192(1), p. 53, 2000; Eur. J. Immunol., 30(4), p. 1040, 2000) was identified as the third costimulatory signal transduction molecule that transduces a second signal (costimulatory signal) necessary for the activation of lymphocytes such as T cells, and coupled with the signal, regulates the function of activated lymphocytes such as activated T cells.
Based on the findings from recent studies relating to this molecule, the AILIM molecule is predicted to be possibly involved in various diseases (for example, autoimmune diseases, allergies, and inflammations) caused by the activation of immunocompetent cells such as T cells (especially T cells). However, there are no reports whatsoever on the relationship between the functional modulation of the AILIM molecule and graft rejection (immunological rejection) accompanying tissue or organ transplantation, as well as attempts to suppress, treat, or prevent such rejection reactions accompanying tissue or organ transplantation by modulating the activity of the AILIM molecule.
In addition, a novel molecule called B7h, B7RP-1, GL50, or LICOS which is considered to be a ligand interacting with the costimulatory signal transduction molecule AILIM has been identified very recently (Nature. Vol. 402, No. 6763, pp. 827-832, 1999; Nature Medicine, Vol. 5, No. 12, pp. 1365-1369, 1999; J. Immunology, Vol. 164, pp. 1653-1657, 2000; Curr. Biol., Vol. 10, No. 6, pp. 333-336, 2000).
The identification of these two kinds of novel molecules, namely AILIM (ICOS) and B7RP-1 (B7h, GL50, LICOS), revealed that, in addition to the known first and second signal transduction pathways between CD28 and CD80 (B7-1)/CD86 (B7-2) and between CTLA4 and CD80 (B7-1)/CD 86 (B7-2), there is a novel third costimulatory signal transduction pathway that is essential for the above mentioned activation of lymphocytes such as T cells and the control of the function of activated T cells, which functions through the interaction between AILIM (ICOS) and B7RP-1 (B7h, GL50, LICOS).
Exhaustive studies are in progress on the biological functions of these novel molecules, the regulation of functions of lymphocytes such as T cells through the third costimulatory signal transduction by the molecules, and the relationship between the novel signal transduction and diseases.